Viruses, including HIV, EBV, and CMV, are potent inducers of T cell responses, resulting in hyperplasia of lymphoid organs and the generation of high levels of CD8+ cytotoxic T lymphocytes (CTL). We have found, using mice infected with lymphocytic choriomeningitis virus (LCMV), that the massive T cell response is primarily virus-specific, with little indication of "bystander proliferation" of T cells lacking specificity for the virus. However, we have shown that n:any of the virus-induced T cells have dual specificity and often recognize targets in addition to the virus-infected syngeneic targets that are stimulating them. These include uninfected allogeneic targets and syngeneic targets infected with putatively unrelated heterologous viruses. The T cell repertoire remains substantially skewed with virus-specific T cells long after clearance of a virus infection, and the introduction of another virus into this skewed repertoire results in the expansion of many T cells crossreactive between the two viruses. Subsequent to the second infection there is a quantitative reduction and qualitative alteration of T cell memory to the first virus after the immune system reaches homeostasis. Our analyses have indicated that T cells exist as a network of cells continually being modulated by crossreactive stimulations and apoptotic deletions, and that how one responds to a virus infection will depend on one's history of exposure to putatively unrelated antigens. The purpose of this grant is to examine the roles of crossreactive T cells vs. bystander events during viral infections by: (1) analyzing the evolution of the T cell repertoire during viral infections; (2) defining the specificity of crossreactive CTL responses between LCMV and other viruses, including Pichinde virus; (3) determining whether bystander events contribute to cytolytic activation or T cell accumulation; (4) determining how the T cell repertoire and pre-existing memory pool is modulated as a consequence of heterologous infections; and (5) examining the role of crossreactive T cells in viral pathogenesis and allograft rejection.